Immunodeficiency with hyper IgM type 1

Other Names: X-linked hyper IgM syndrome; Hyper IgM immunodeficiency, x-linked; Hyper IgM syndrome; Hyper IgM syndrome 1; XHIM; HIGM; IHIS; HIGM1

Hyper IgM syndrome is a type of primary immunodeficiency syndrome. Primary immunodeficiency occurs when part of a person’s immune system is missing or does not work correctly. The bodies of people with primary immunodeficiency can’t get rid of germs or protect themselves from new germs as well as they should. Primary immunodeficiencies are inherited, meaning they are passed down from parents to children.

People with this disorder have abnormal levels of proteins called antibodies or immunoglobulins. Antibodies help protect the body against infection by attaching to specific foreign particles and germs, marking them for destruction. There are several classes of antibodies, and each one has a different function in the immune system. Although the name of this condition implies that affected individuals always have high levels of immunoglobulin M (IgM), some people have normal levels of this antibody. People with X-linked hyper IgM syndrome have low levels of three other classes of antibodies: immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin E (IgE). The lack of certain antibody classes makes it difficult for people with this disorder to fight off infections.

Epidemiology

X-linked hyper IgM syndrome is estimated to occur in 2 per million newborn boys.

Cause

Mutations in the CD40LG gene cause X-linked hyper IgM syndrome. This gene provides instructions for making a protein called CD40 ligand, which is found on the surface of immune system cells known as T cells. CD40 ligand attaches like a key in a lock to its receptor protein, which is located on the surface of immune system cells called B cells. B cells are involved in the production of antibodies, and initially they are able to make only IgM antibodies. When CD40 ligand and its receptor protein are connected, they trigger a series of chemical signals that instruct the B cell to start making IgG, IgA, or IgE antibodies.

CD40 ligand is also necessary for T cells to interact with other cells of the immune system, and it plays a key role in T cell differentiation (the process by which cells mature to carry out specific functions).

Mutations in the CD40LG gene lead to the production of an abnormal CD40 ligand or prevent production of this protein. If CD40 ligand does not attach to its receptor on B cells, these cells cannot produce IgG, IgA, or IgE antibodies. Mutations in the CD40LG gene also impair the T cell's ability to differentiate and interact with other immune system cells. People with X-linked hyper IgM syndrome are more susceptible to infections because they do not have a properly functioning immune system.

Inheritance

X-linked recessive inheritance

This condition is inherited in an X-linked recessive pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Signs and symptoms

Symptoms and physical findings associated with hyper IgM syndrome usually become apparent in the first or second year of life. This condition may be characterized by recurrent pus-producing (pyogenic) bacterial infections of the upper and lower respiratory tract including the sinuses (sinusitis) and/or the lungs (pneumonitis or pneumonia); the middle ear (otitis media); the membrane that lines the eyelids and the white portions (sclera) of the eyes (conjunctivitis); the skin (pyoderma); and/or, in some cases, other areas.

Other signs of the disease include enlarged tonsils, liver, and spleen, chronic diarrhea, and an increased risk of unusual or “opportunistic” infections and non-Hodgkins lymphoma. Opportunistic infections are infections caused by microorganisms that usually do not cause disease in individuals with fully functioning immune systems (non-immunocompromised) or widespread (systemic) overwhelming disease by microorganisms that typically cause only localized, mild infections. In individuals with Hyper-IgM Syndrome, such opportunistic infections may include those caused by Pneumocystis carinii, a microorganism that causes a form of pneumonia, or Cryptosporidium, a single-celled parasite (protozoa) that can cause infections of the intestinal tract.

In addition, individuals with Hyper-IgM Syndrome are prone to certain autoimmune disorders affecting particular elements of the blood. Autoimmune attacks on red blood cells lead to anemia, while autoimmune destruction of infection-fighting neutrophils further increases the risk of infection.

The range and severity of symptoms and physical features associated with this disorder may vary from case to case.

Diagnosis

X-linked hyper IgM syndrome (HIGM1) should be suspected in any male presenting with Pneumocystis jirovecii pneumonia, persistent Cryptosporidium diarrhea, recurrent upper- and lower-respiratory tract bacterial infections, neutropenia, sclerosing cholangitis, and associated bile duct tumors with the following laboratory abnormalities:

• Absent or low serum concentrations of IgG and IgA
• Normal or elevated serum concentrations of IgM

Normal:

• Number and distribution of T, B, and NK lymphocyte subsets
• T-cell proliferation in response to mitogens
• Decreased expression of CD40L on the surface of activated CD4 cells (not universal)
• Establishing the Diagnosis
• The diagnosis of HIGM1 is established in a male proband with typical clinical and laboratory findings by identification of a hemizygous pathogenic variant in CD40LG on molecular genetic testing.

Treatment

Hematopoietic stem cell transplantation (HSCT) (the only curative treatment currently available), ideally performed before age ten years, prior to evidence of organ damage; immunoglobulin replacement therapy (either intravenous or subcutaneous); appropriate antimicrobial therapy for acute infections; antimicrobial prophylaxis for opportunistic infection against Pneumocysitis jirovecii pneumonia; recombinant granulocyte colony-stimulating factor for chronic neutropenia; immunosuppressants for autoimmune disorders.

Agents/circumstances to avoid: Areas that place individual at risk of contracting Cryptosporidium including pools, lakes, ponds, or certain water sources; drinking unpurified or unfiltered water; live vaccines such as rotavirus, MMR, varicella, live attenuated polio, and BCG.

NIH genetic and rare disease info

• NIH info on Immunodeficiency with hyper IgM type 1

Immunodeficiency with hyper IgM type 1 is a rare disease.

Immunodeficiency with hyper IgM type 1 Resources
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